CD30 is a 105-120 kDa integral membrane glycoprotein and a member of the tumor necrosis factor receptor (TNF-R) superfamily. Under normal conditions expression of CD30 is restricted to activated T and B cells and absent from resting lymphocytes, resting monocytes and from normal cells outside of the immune system. CD30 expression in tissues where it is normally absent has been linked to several disease states. Originally identified on Reed-Sternberg cells in Hodgkin's disease (HD or Hodgkin's lymphoma) using the Ki-1 monoclonal antibody (mAb) (Stein et al., 1985, Blood, 66, 848-858; Laudewitz et al, 1986, J. Invest. Dermatol. 86:350-354), CD30 has also been shown to be expressed on a subset of non-Hodgkin's lymphomas (NHL), including Burkitt's lymphoma, anaplastic large-cell lymphomas (ALCL), cutaneous T-cell lymphomas, nodular small cleaved-cell lymphomas, lymphocytic lymphomas, peripheral T-cell lymphomas, Lennert's lymphomas, immunoblastic lymphomas, T-cell leukemia/lymphomas (ATLL), adult T-cell leukemia (T-ALL), and entroblastic/centrocytic (cb/cc) follicular lymphomas (Stein et al., Blood 66:848 (1985); Miettinen, Arch. Pathol. Lab. Med. 116:1197 (1992); Piris et al., Histopathology 17:211 (1990); Bums et al., Am. J. Clin. Pathol. 93:327(1990); and Eckert et al., Am. J. Dermatopathol. 11:345 (1989)), as well as several virally-transformed lines such as human T-Cell Lymphotrophic Virus I or II transformed T-cells, and Epstein-Barr Virus transformed B-cells (Stein et al., Blood 66:848 (1985); Andreesen et al., Blood 63:1299 (1984)). In addition, CD30 expression has been documented in embryonal carcinomas, nonembryonal carcinomas, malignant melanomas, mesenchymal tumors, and myeloid cell lines and macrophages at late stages of differentiation (Schwarting et al., Blood 74:1678 (1989); Pallesen et al., Am J. Pathol. 133:446 (1988); Mechtersheimer et al., Cancer 66:1732 (1990); Andreesen et al., Am. J. Pathol. 134:187 (1989)). CD30 is also expressed at high levels by activated cells in autoimmune disease.
The percentage of CD30 positive cells in normal individuals is relatively small, rendering CD30 an ideal marker of disease and target for antibody-mediated therapy. Accordingly, CD30 is widely used as a clinical marker and therapeutic target for Hodgkin's disease (HD). Monoclonal antibodies specific for the CD30 antigen have been explored as vehicles for the delivery of cytostatic drugs, plant toxins and radioisotopes in both pre-clinical models and clinical studies (Engert et al., 1990, Cancer Research 50:84-88; Barth et al., 2000, Blood 95:3909-3914). In patients with HD, targeting of the CD30 antigen was achieved with low doses of the anti-CD30 mAb, BerH2 (Falini et al., 1992, British Journal of Haematology 82:38-45). In a subsequent clinical trial, a toxin (saporin) was chemically conjugated to the antibody BerH2 and all four patients demonstrated reductions in tumor mass (Falini et al., 1992, Lancet 339:1195-1196). Similarly, anti-CD30 antibodies conjugated with deglycosylated ricin A-chain toxin were found effective in inhibiting the progression of Hodgkin's disease (Schnell, R. et al. 2003, Annals of Oncology, 14, 729). Anti-CD30 antibodies, their conjugates, and corresponding immunotherapic methods are further reported in U.S. Pat. App. Pub. Nos. 2005/0123536, 2004/0018194, and 2004/0006215; as well as WO 2006/039644, WO 2005/001038, and WO 2003/043661. Despite the initial promising results, liver toxicity and vascular leak syndrome associated with immunotoxin therapy potentially limits the ability to deliver curative doses of these agents (Tsutsumi et al., 2000, Proc. Nat'l Acad. Sci. U.S.A. 97:8545-8553).
CD30 is endoproteolytically cleaved to form circulating, soluble protein. Soluble CD30 (sCD30) is detectable in the circulation of patients suffering from diseases including rheumatoid arthritis (Gerli et al., 2000, J. Immunol. 164, 4399-4407), multiple sclerosis (McMillan et al. 2000, Acta Neurol. Scand. 101 :239-243) and systemic sclerosis (Ihn et al., J. Rheumatol. 27:698-702). Serum level of sCD30 in patients suffering from Hodgkin's disease (HD) was found to be a prognostic indicator of the disease (Nadali, G. et al. 1998, Blood. 91(8), 3011), and shedding of CD30 has also been detected in anaplastic large-cell lymphoma (ALCL) as well as adult T-cell leukemia (ATL). Shedding of CD30 is mediated by the metalloprotease TACE (ADAM17) (Hansen, H. P. et al. 2000, J. of Immunol. 6704-6709).
It has been postulated that shedding of the CD30 extracellular antigen domain inhibits the effectiveness of immunotherapy and contributes to side effects such as organ toxicity and vascular leak syndrome. In one preclinical rodent study, anti-CD30 immunotoxins were administered concomitantly with the hydroxamate metalloprotease inhibitor BB-3644 (Matthey, B. et al., 2004, Int. J. Cancer, 111, 568). It was found that the combination was substantially more effective both in vitro and in vivo than treatment with immunotoxin alone. An earlier in vitro study along the same lines had similar results (Hansen et al., 2002, Int. J. Cancer, 98, 210).
In view of the above findings, there is a continuing need to improve the effectiveness of immunotherapy in connection with CD30 positive diseases. The methods and compositions herein related to combinations of immunotherapeutics with sheddase inhibitors help provide for this ongoing need.